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PACS‐1 binding to adaptors is required for acidic cluster motif‐mediated protein traffic
Author(s) -
Crump Colin M.,
Xiang Yang,
Thomas Laurel,
Gu Feng,
Austin Carol,
Tooze Sharon A.,
Thomas Gary
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.9.2191
Subject(s) - biology , signal transducing adaptor protein , furin , microbiology and biotechnology , biogenesis , golgi apparatus , plasma protein binding , endosome , sequence motif , clathrin , biochemistry , receptor , phosphorylation , endocytosis , gene , endoplasmic reticulum , intracellular , enzyme
PACS‐1 is a cytosolic protein involved in controlling the correct subcellular localization of integral membrane proteins that contain acidic cluster sorting motifs, such as furin and human immunodeficiency virus type 1 (HIV‐1) Nef. We have now investigated the interaction of PACS‐1 with heterotetrameric adaptor complexes. PACS‐1 associates with both AP‐1 and AP‐3, but not AP‐2, and forms a ternary complex between furin and AP‐1. A short sequence within PACS‐1 that is essential for binding to AP‐1 has been identified. Mutation of this motif yielded a dominant‐negative PACS‐1 molecule that can still bind to acidic cluster motifs on cargo proteins but not to adaptor complexes. Expression of dominant‐negative PACS‐1 causes a mislocalization of both furin and mannose 6‐phosphate receptor from the trans ‐Golgi network, but has no effect on the localization of proteins that do not contain acidic cluster sorting motifs. Furthermore, expression of dominant‐negative PACS‐1 inhibits the ability of HIV‐1 Nef to downregulate MHC‐I. These studies demonstrate the requirement for PACS‐1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV‐1 pathogenesis.